BG99893A - Foaming tablets and granules and method for their preparation - Google Patents

Abstract

PCT No. PCT/HU94/00006 Sec. 371 Date Sep. 7, 1995 Sec. 102(e) Date Sep. 7, 1995 PCT Filed Mar. 10, 1994 PCT Pub. No. WO94/20077 PCT Pub. Date Sep. 15, 1994The invention relates to effervescent tablets and granules comprising a shell material, a basic sparkling component, an acidic sparkling component, and a sweetening agent, macro- and microelements and vitamins as active agents. The effervescent tablets and granules comprise 20-50% by mass of mannitol as shell material, 8-25% by mass of potassium hydrogen carbonate as basic sparkling component, 9-27% by mass of malic acid as acidic sparkling component, and 0.4-2.2% by mass of aspartame as sweetening agent. Furthermore, the invention relates to a process for preparing the above-described effervescent tablets and granules.

Description

The invention relates to foaming tablets and granules which do not contain sugar and sodium and to a method for their preparation.

In particular, the invention relates to foaming tablets and granules containing a coating substance, a basic foaming and disintegrating (hereinafter referred to as aerated) ingredient, an acidic aerating ingredient and a sweetener, in addition macro and trace elements and optionally vitamins. The invention further relates to a method for preparing such tablets and granules.

It is known that one of the most popular pharmaceutical forms for the introduction of medicines, vitamins and minerals into the body is the so-called foam tablet (Pharmaceutical Dosage Form: Tablets, Vol. I., 2nd edition, A. Lieberman ed., 1989, Marcel Dekker, Inc.). The development of this form is supported in terms of the pharmaceutical effect, in addition to commercial reasons, by several factors, e.g. reducing gastric irritability, increasing absorption, etc. The solution of such tablets in water is a carbonated carbonated beverage.

The effective disintegration of the foaming tablets is caused by a mixture consisting of an acid and a base, with said mixture nearly cracking the tablet in contact with water until carbon dioxide is released.

The production and packaging of foaming tablets requires great care; therefore, direct compression over the wet method is preferred in practice.

Most of the foam tablets contain three main ingredients in addition to the active substance: a coating and binder, an acid extinguishing agent and a basic extinguishing agent.

Usually sugars (lactose, sucrose, glucose), sorbitol, xylitol or starch are used for the binder and the binder, as acidic extinguishing agent - citric acid, tartaric acid, fumaric acid or adipic acid, and as basic extinguishing agent - sodium hydrogen carbonate and magnesium carbonate. carbonate.

Of the other ingredients commonly used in the foaming tablet, the following preferred agents may be mentioned: sweeteners such as sugars, saccharin, sodium cyclamate and aspartame; flavor enhancers and flavors; lubricants such as polyethylene glycols, silicone oils, stearates and adipic acid.

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US Pat. 4, 725, 427 describes a foam tablet which contains lactose as a coating material, as citric acid as a carbonating agent, as a basic carbonating ingredient a mixture of sodium hydrogen carbonate and potassium hydrogen carbonate and aspartame as a sweetener. In addition to water and fat soluble vitamins, this tablet contains inorganic substances as active agents and these substances have been made bioavailable by use in chelating form. However, this composition does not allow the production of sodium-free tablets, which is a significant drawback, since it is well known that the introduction of excess sodium into the body has various harmful physiological effects. Another disadvantage of this composition is the presence of citric acid in an amount of 20-45 wt.%, Since a large amount of this acid can cause harmful physiological effects.

U.S. Pat. 4, 678, 661 describes foaming tablets containing a mixture of calcium carbonate and potassium carbonate as the main carbonating ingredient. A major drawback of this tablet is that it has the undesirable soap taste of potassium hydrogen carbonate. In addition, the use of calcium carbonate has a negative effect on the dissolution time.

U.S. Pat. No. 4, 704, 269 describes a foam tablet containing potassium hydrogen carbonate as the main carbonating ingredient, malic and citric acid as acidic carbonating constituents, a mixture of sorbitol and maltodextrin as a coating and binder and calcium sugars as a sweetener. This composition is used as an anti-acid agent and as an analgesic; its deficiency is due to the presence of sorbitol and its storage is not satisfactory. In addition, sorbitol is not recommended for general use in beverages, as some individuals have low tolerance to it (Martindale: The Extra Pharmacopoeia, 19th ed., London, 1989, p. 1274).

The object of the invention is to provide foaming tablets and granules that are chemically stable, easily compressible, have favorable physical properties, contain no sodium and sugar, and contain macro and trace elements and possibly vitamins homogeneously distributed.

The invention is based on the assumption that the above task can be fully achieved by using the following major ingredients for the preparation of foaming tablets and granules: mannitol as a coating material, malic acid as an acidic carbonate, potassium hydrogen carbonate as a major carbonating agent ingredient and aspartame - as a sweetener.

In addition, the invention is based on the assumption that the use of mannitol allows the introduction of salts of macro and microelements with a high crystalline water content. Therefore, the invention overcomes the technical premise that foaming tablets and granules cannot be obtained from such materials as is known so far, due to the fact that the high water content inhibits the compression and, at the same time, the premature liquidation of the tablets is achieved.

Another basis of the invention is the assumption that when using mannitol for the preparation of tablets or granules, macro- and trace elements form complexes with it, through which the incompatibility of the components can be eliminated in the process, a chemically stable end product is obtained and the mannitol obtained complexes can be more easily absorbed by the body, which means that they become more applicable.

Another basis of the invention is the assumption that, when used together with mannitol, malic acid and aspartame, *. ·. ·. _{k l} potassium hydrogen carbonate can be used even alone as basic carbonating ingredient, whereby it becomes possible to eliminate the sodium ions from the composition. In addition, such a combination can avoid the unwanted taste and humidity of potassium hydrogen carbonate. Moreover, poor composition of the potassium hydrogen carbonate for compression can be avoided in this composition, i.e., the property of sticking to the surface of prints and dies, which makes it impossible to press it in places with relative humidity of 45% or more. Therefore, even in this regard, the invention overcomes a technical prejudice. This claim is supported by the fact that US patent no. 4, 678, 661 in column 1, lines 27-32 contains the following statement: The use of potassium bicarbonate and potassium carbonate alone is not appropriate because, first, potassium compounds give the substances an unpleasant soapy taste and secondly, that they are sensitive to moisture, the introduction of potassium salts creates major technical problems.

Another basis for the invention is the assumption that, when combined with malic acid as an acidic carbonating ingredient and mannitol, a suitable compression formulation is obtained. This assumption is surprising as it is known that malic acid itself cannot be compressed easily and, because of its low melting point, it is a difficult-to-treat compound that melts during milling. On the other hand, the use of malic acid in relatively high amounts is made possible by our assumption, while at the same time the antioxidant and taste-enhancing effect of malic acid, as well as its ability to optimally adjust the pH, can be used.

Finally, the invention is based on the assumption that the combined use of mannitol, potassium hydrogen carbonate, malic acid and aspartame allows the preparation of a low calorie composition which does not lead to gastrointestinal complaints. The tablets obtained from this composition have a very high cracking force and a quick aeration and clear solution are achieved, even if the composition contains incompatible vitamins, macronutrients and constituents (potassium hydrogen carbonate, malic acid, salts of macronutrients and micronutrients with high crystalline water content) having inherently poor compression properties.

On the basis of the above, the invention relates to tablets and granules containing a coating material, a basic carbonating ingredient, an acidic carbonating ingredient and a sweetener, in addition macro and trace elements and optionally vitamins as active substances. According to the invention, the foaming tablets and granules include 20-50 wt.%, Preferably 30-40 wt.% Mannitol as a coating material, 8-25 wt.%, Preferably 14-18 wt.% Potassium hydrogen carbonate as the main carbonating ingredient, 9 -27 wt.%, Preferably 15-21 wt.% Malic acid as an acidic carbonating ingredient and 0.4-2.2 wt.%, Predominantly 0.6-1.5% aspartame as a sweetener, moreover, if desired, flavoring, lubricating and other additives commonly used in the manufacture of foaming tablets, in an amount sufficient to supplement the weight of the ingredients up to 100%.

The invention further relates to a process for the preparation of foaming tablets or granules. According to the invention, 20-50% by weight, preferably 30-40% by weight of mannitol, 8-25%, preferably 14-18% by weight of potassium hydrogen carbonate, 9-24%, preferably 15-21%, are homogenized. % malic acid and 0.4-2-2-% by weight, mainly 0.6-1.5% by weight aspartame together with macro- and trace elements and vitamins that • · · · ·· · · ♦ <

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The foaming tablets and granules according to the invention contain, as macro- and microelements, mainly magnesium, zinc, iron (II), copper (II), manganese (II) and chromium (III) cations, in addition molybdenum (VI) and selenium (IV) anions.

The iron ions are used mainly in the form of iron (II) sulfate heptahydrate, zinc ions in the form of zinc sulfate heptahydrate, copper ions in the form of copper sulfate pentahydrate, manganese ions in the form of manganese sulfate monohydrates, - in the form of ammonium heptamolybdenum tetrahydrate, selenium ions in the form of selenium acid, magnesium ions in the form of magnesium sulfate heptahydrate, and chromium ions in the form of chromium (III) chloride hexahydrate.

Vitamins are added to the composition mainly in the following amounts: 0.01-0.5 wt% vitamin B 0.01-0.25 wt% vitamin B ₂ , 0.01-0.5 wt% vitamin B ₆ , 0.001-0.01 wt% vitamin B ₁₂ , 0- 1-2 wt% nicotinamide, 0.01-0.5 wt% vitamin A, 0.0015-0.015 wt% vitamin D, 0.1-5 wt% vitamin C, 0.01-0.1 wt% folic acid, 0.1-0.5 wt% pantothenic acid, 0.01-7 wt.% vitamin E and 0.001-0.01 wt.% vitamin H.

In addition to the macronutrients and vitamins, the tablets of the invention may also contain flavoring and flavoring agents such as orange, lemon or pineapple aroma, lubricants such as polyethylene glycols, silicone oils, stearates or adipic acid, absorption enhancers · · · · · · · ·.

** · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · As tartaric acid and glycine, plus any other additives commonly used in the manufacture of foam tablets.

The main advantages of the invention are as follows:

a) The tablets are chemically stable, easy to compress and exhibit excellent physical properties.

(b) Tablets and granules contain the active substances which are macro- and trace elements, as well as vitamins, all homogeneously distributed.

c) Upon dissolution of the tablets in water, a clear, pleasant-tasting drink is obtained without any precipitate.

d) The presence of mannitol makes it possible to use malic acid as an acidic carbonating ingredient in relatively large quantities, thereby enhancing the effects of the acid for favorable antioxidant and taste enhancement and optimal pH adjustment.

e) Using mannitol, low-calorie, low-calorie foam tablets, rich in macronutrients and vitamins, can be prepared and can also be consumed by diabetics.

f) In known foaming tablets containing vitamins and minerals, trace elements are used in the form of compounds which do not contain crystalline water or contain a small amount of crystalline water. On the other hand, the invention makes it possible to use substances with a high crystalline water content which, by themselves, are poorly pressed or not compressible at all, which are the most stable modifications of inorganic compounds and can therefore be prepared or obtained at low price and high purity.

(g) When mannitol, malic acid and aspartame are combined, the homogeneous distribution of macronutrients and vitamins may occur even when the amount of the tablet is very low in weight. In the process, homogeneous distribution of vitamins is ensured without adversely affecting the properties of these sensitive compounds.

h) The invention provides foaming tablets containing incompatible active substances such as vitamins as well as macro- and trace elements.

i) In the manufacture of tablets, macro and microelements form complexes with mannitol, whereby the chemical stability of the tablet, as well as the absorption and biological properties of the active substances, are made more favorable.

j) The invention provides the preparation of tablets using aerated constituents (potassium hydrogen carbonate and malic acid) and inorganic constituents with high crystalline water content (sources of macro- and microelements) which, due to their unfavorable properties, could not be used earlier in the production of foam tablets. In addition, the foaming tablets thus obtained have a high cracking force and give a clear solution with a short aeration period.

The invention is further illustrated by the following non-limiting examples.

Example 1

Ready-to-press pellets consist of four pellets and so-called outer phase.

Granule I

Vitamin B ₁ 7.29 g • · · · · · · · · ·

Vitamin B ₉ 7.50 g Vitamin B ₆ 10. 94 g Co-pantothenate 38. 215g nicotinamide 85.00 g mannitol 500. 00 g After sieving the materials homogenize, mix with ethanol, granulate then the wet granules are dried and dried granulate again. Granule II iron (II) sulfate heptahydrate 99.55 g malic acid 1500.00 g mannitol 1500. 00 g After pressing the materials homogenize, mix with distilled water, granulated, dried, granulated again and finally they are dried. Granule III potassium hydrogen carbonate 3800. 00 g mannitol 3800. 00 g

After sieving and homogenizing, the mass is mixed with a mixture of water and ethanol, then granulated again after drying.

Granule IV

mannitol 3925.00 Mr Günter magnesium sulfate heptahydrate 1571.50 Mr Günter glycine 150.00 Mr Günter succinic acid 250.00 Mr Günter mannitol 75.00 Mr Günter selenium acid 0.1635 Mr Günter ammonium heptamolybdate tetrahydrate 0.690 Mr Günter

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• * * ♦ * * · · · »• · · · · · · · · · · · Magnesium (P) -sulfate monohydrate 15.38g copper (P) -sulphate pentahydrate 29.47g zinc sulfate heptahydrate 219.95g

After grinding, homogenizing and mixing, the mass is granulated with distilled water, then dried, granulated again and finally dried.

Exterior phase materials Vitamin C 300. 00 g malic acid 3000. 00 g polyethylene glycol 710. 00 g aspartame 200. 00 g lemon scent 1000. 00 g

After sieving and milling, the materials of the outer phase are homogenized. The preliminary homogenate thus obtained is mixed with granules I, Π, II and IV and the resulting mixture homogenized. From the granules thus obtained, about 5000 tablets with a diameter of 32 mm and an average weight of 4.5 g were pressed.

Example 2

It is done as in Example 1 except that the vitamins are supplemented with Vitamin E and the amounts of the ingredients are changed as follows:

Name of the constituents Quantity (g) iron (II) sulfate heptahydrate (FeSO ₄ .7H ₂ O) 99.56 Zinc (II) sulfate (ZnSO ₄ .7H ₂ O) 109.97 Copper (II) sulfate (CuSO ₄ .5H ₂ O) 14.74 Manganese (II) sulphate (MnSO ₄ .H ₂ O) 7.69 ammonium molybdenate [(NH ₄ ) ₆ Mo ₇ O ₂₄ .4H ₂ O] 0.276 • ·

selenium acid (H ₂ SeO ₃ ) magnesium sulfate (MgSO ₄ .7H ₂ O) 0.082 608.34 vitamin B ^ (thiamine. HCl) vitamin B ₂ (riboflavin) vitamin B ₆ (pyridoxine. HCl) nicotinamide vitamin C [b - (+) - ascorbic acid] pantothenic acid (Ca-pantothenate) vitamin E (DL-α-tocopherol) ) 3 3.5 4 40 175 15 25 succinic acid glycine malic acid potassium bicarbonate (CNSO _X ) mannitol 100 75 2750 2300 6500 aspartame pineapple flavor polyethylene glycol 200 1000 750

Of the granules ready for compression, about 5000 tablets are prepared with a diameter of 25 mm and an average weight of 3 g.

Example 3

It is done as in Example 1 except that the trace elements are supplemented with chromium and the vitamins are supplemented with vitamin B ₁₂ , A, D and H and folic acid, in addition, the quantities of the components are changed as follows:

Name of the constituents iron (II) sulphate heptahydrate (FeSO ₄ .7H ₂ O) Quantity (g) 373.35

zinc (II) sulfate (ZnSO ₄ .7H ₂ O) 329.97 copper (II) sulfate (CuSO ₄ .5H ₂ O) 39.29 manganese (II) sulfate (MnSO ₄ .H ₂ O) 38.46 ammonium molybdenate [(ΝΗ ₄₎ ^ ΜθγΟ ₂₄ .4Η ₂ Ο] 1.38 selenious acid (H ^ SeO ^) 0.2 magnesium sulphate (MgSO ₄ .7H ₂ O) 5069.5 chromium (III) -chloride (SgS1 ₃ .6N ₂ O?) 1.28 vitamin B ₁ ( thiamine HC1) 7.5 vitamin B ₂ (riboflavin) 8.5 vitamin B ^ (pyridoxine. HC1) 10 vitamin B ₁₂ (cyanocobalamin) 0.01 nicotinamide95 vitamin A5 vitamin D0.05 vitamin C [b - (+) - ascorbic acid] 450 folic acid 450 pantothenic acid (Ca-pantothenate) 35 vitamin E (DL-α-tocopherol) 50 vitamin H (biotin) 325 succinic acid300 glycine180 malic acid6000 potassium hydrochloride drogen carbonate (CNSSC) 5000 mannitol 11500

300 1500 2000 aspartame orange flavor polyethylene glycol • · ·

From the ready-to-press pellets, about 5000 tablets with a diameter of 35 mm and a weight of 6.6 g are prepared.

Example 4

It was done as in Example 3 except that the amount of malic acid was changed to 3500 g, that of potassium hydrogen carbonate to 2800 g, that of mannitol to 16,000 g and that of aspartame to 150 g. The ready-to-press pellets yield 5000 tablets with a diameter of 32 mm and an average weight of 6.6. Mr Rücker

Example 5

It was done as in Example 3 except that the amount of malic acid was changed to 10000 g, that of potassium hydrogen carbonate to 9000 g, that of mannitol to 8000 g and that of aspartame to 800 g. The ready-to-press pellets yield 5000 tablets with a diameter of 32 mm and an average weight of 7.7. Mr Rücker

Claims (7)

1. Foaming tablets and granules containing a coating material, a basic carbonating ingredient, an acidic carbonating ingredient and a sweetener, in addition macro- and trace elements and optionally vitamins as active substances, including 20-50% by weight, mannitol as a coating material , 8-25 wt.% Potassium hydrogen carbonate as the main aerating ingredient, 9-27 wt.% Malic acid as an acidic aerating ingredient and 0.4-2.2 wt.% Aspartame as a sweetener, in addition possibly flavoring, lubricating and other additives commonly used in production of foaming table tki in an amount sufficient to supplement the mass of the components to 100%. Foaming tablets or granules according to claim 1, which include 30-40 wt.% Mannitol, 14-18 wt.% Potassium hydrogen carbonate, 15-21 wt.% Malic acid and 0.6-1.5 wt.% Aspartame. Foaming tablets or granules according to claim 1, which include, as macro and trace elements, magnesium, zinc, iron (II), copper (II), manganese (II) and chromium (III) cations, in addition molybdenum (Y1) and selenium (1U) anions. 4. Foaming tablets or granules according to claim 1, wherein the iron ions are present in the form of ferrous sulfate heptahydrate, zinc ions in the form of zinc sulfate heptahydrate, copper ions in the form of copper sulfate pentahydrate, manganese ions in the form of manganese ions sulfate monohydrate, molybdenum ions in the form of ammonium heptamolybdate tetrahydrate, selenium ions in the form of selenium acid, magnesium ions in the form of magnesium sulfate heptahydrate, and chromium ions in the form of chromium (III) chloride hex hydrate. • · · Ί 5. Foaming tablets or granules according to claim 1, wherein the vitamins are in the following amounts by weight of the composition: 0.01-0.5 wt% vitamin B 0.01-0.25 wt% vitamin B ₂ , 0.01-0.5 wt% vitamin B ₆ , 0.001-0.01 wt% vitamin B ₁₂ , 0.1-2 wt% nicotinamide, 0.01-0.5 wt% vitamin A, 0.0015-0.015 wt% vitamin D, 0.1-5 wt% vitamin C, 0.01- 0.1 wt% folic acid, 0.1-0.5 wt% pantothenic acid, 0.01-7 wt% vitamin E and 0.001-0.01 wt% vitamin H. 6. A process for the preparation of foaming tablets or granules, comprising the steps of homogenizing 20-50 wt.% Mannitol, 8-25 wt.% Potassium hydrogen carbonate, 9-24 wt.% Malic acid and 0.4 -2.2% by weight of aspartame together with the macronutrients and vitamins and vitamins to be introduced and optionally together with flavoring, lubricating and other additives commonly used in the manufacture of foaming tablets, then granulating the homogenisate thus obtained to granules, ready for compression and finally compression of tablets or granules with jelly size and strength. Method according to claim 6, characterized in that 30-40 wt.% Mannitol, 14-18 wt.% Potassium hydrogen carbonate, 15-21 wt.% Malic acid and 0.6-1.5 wt.% Aspartame are homogenized with the other ingredients of the tablet.